A number of observations have suggested that host lymphocytes, specifically cytotoxic T cells (CTL) play a significant role in mediating allogeneic marrow graft rejection. In a murine model system, CTL were cloned from the spleens of sublethally irradiated animals which had rejected MHC disparate marrow grafts. It was found that cloned CTL were sufficient to effect rejection of T cell depleted allogeneic marrow in lethally irradiated animals. The rejection of marrow grafts by CTL was specific for the MHC gene products expressed by the marrow cells and correlated with the cytotoxic specificity of the individual clones. Because host CTL in isolation could reject donor marrow grafts, the ability of cell populations which could suppress host CTL responses to regulate marrow engraftment was studied. Cells with a specific type of suppressor activity, termed veto cells, which might regulate host rejection responses and also mediate self tolerance, have been reported to be present in marrow, and an ability of IL-2 to enhance the activity of veto suppressor cell populations was found. Such cells enhanced engraftment of MHC-mismatched, T cell depleted marrow in vivo. It was found that veto cells exerted their effect by clonal deletion of precursor CTL, and that such clonal elimination involved an active participation by precursor CTL. Specifically, triggering of veto cells was found to be mediated by target cell activation with release of cytolysin which was sufficient to trigger veto cells. These studies suggest a possible new role for cytolysin in the maintenance of self tolerance. In other studies, the role of cytokines in modulation of T cell responses, including mediation of anti-tumor effects, has been evaluated with the finding that tumor-derived TGF-beta can regulate such transplantation responses in vivo. The transcriptional regulator ICER has been identified as important in the modulation of T cell cytokine responses in vitro. A transgenic mouse model will be used to investigate in vivo relevance of these observations. Formerly Z01 CB09287-09 EIB. - cyctotoxicity, immunology, regulation, rejection, T cell, Transplantation,